EP1395616B1 - Complexes de carbene de metaux de transition du groupe 8 utilises comme catalyseurs de metathese d'olefines enantioselective - Google Patents

Complexes de carbene de metaux de transition du groupe 8 utilises comme catalyseurs de metathese d'olefines enantioselective Download PDF

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EP1395616B1
EP1395616B1 EP02762142.4A EP02762142A EP1395616B1 EP 1395616 B1 EP1395616 B1 EP 1395616B1 EP 02762142 A EP02762142 A EP 02762142A EP 1395616 B1 EP1395616 B1 EP 1395616B1
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group
substituted
complex
hydrocarbyl
alkyl
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EP1395616A4 (fr
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Robert H. Grubbs
Donald W. Ward
Thomas J. Seiders
Steven D. Goldberg
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California Institute of Technology CalTech
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/0046—Ruthenium compounds

Definitions

  • This invention relates generally to method for carrying out an olefin metathesis reaction using a chiral Group 8 transition metal complex as a catalyst. More particularly, the invention relates to methods for carrying out enantioselective reactions using the aforementioned catalyst. The invention also relates to the catalyst itself.
  • M is a Group 8 transition metal such as ruthenium or osmium
  • X and X' are anionic ligands
  • L and L' are neutral electron donors
  • metathesis catalysts have been prepared with phosphine ligands, e.g., tricyclohexylphosphine or tricyclopentylphosphine, exemplified by the well-defined, metathesis-active ruthenium alkylidene complexes (II) and (III): wherein "Cy” is a cycloalkyl group such as cyclohexyl or cyclopentyl. See Grubbs et al., U.S. Patent No. 5,917,071 and Trnka et al., supra.
  • N-heterocyclic carbene ligands offer many advantages, including readily tunable steric bulk, vastly increased electron donor character, and compatibility with a variety of metal species.
  • replacement of one of the phosphine ligands in these complexes significantly improves thermal stability in solution.
  • the vast majority of research on these carbene ligands has focused on their generation and isolation, a feat finally accomplished by Arduengo and coworkers within the last ten years (see, e.g., Arduengo et al., Acc. Chem. Res. 32:913-921 (1999 )).
  • ruthenium complexes IVA, (IVB), (VA) and (VB):
  • Cy is as defined previously, Ph represents phenyl, "IMes” represents 1,3-dimesityl-imidazol-2-ylidene: and "IMesH 2 " represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene:
  • IMesH 2 represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene:
  • Other ruthenium-based olefin metathesis catalysts formed with N-heterocyclic carbene ligands are known.
  • transition metal carbene complexes particularly those containing a ligand having the 4,5-dihydroimidazol-2-ylidene structure such as in IMesH 2 . have been found to address a number of previously unsolved problems in olefin metathesis reactions, particularly cross-metathesis reactions.
  • Group 8-catalyzed olefin metathesis such as ring-closing metathesis
  • the molybdenum-based catalysts are limited since these systems lack extensive functional group tolerance and require rigorous exclusion of air and moisture.
  • chiral ruthenium carbene complexes of the invention exhibit high enantioselectivity, for example up to 90% ee in the ring-closing metathesis of achiral trienes. While chiral N-heterocyclic carbene ruthenium complexes have been reported previously ( Scholl et al., Org. Lett. 1:953-956 (1999 ) and Weskamp et al.,Angew. Chem. Int. Ed. 37:2490-2493 (1998 )), none report their use in asymmetric metathesis.
  • WO 00/71554 A2 generally concerns imidazolidine-based metal carbene methathesis catalysts. WO 00/71554 A2 does not, however, disclose any stereochemistry for the imidazolidine ligands, or the use of such chiral catalysts for asymmetric metathesis.
  • One aspect of the invention pertains to a chiral ruthenium carbene complex of the formula (VII): wherein:
  • Another aspect of the invention pertains to a method of controlling the enantioselectivity of an olefin metathesis reaction comprising catalyzing the reaction with a chiral ruthenium carbene complex as defined herein above.
  • the present invention is addressed to the aforementioned needs in the art, and provides a novel chiral ruthenium carbene complex and a novel process for using the chiral complexes to catalyze a variety of olefin metathesis reactions, including cross-metathesis reactions.
  • Such complexes are highly active catalysts of olefin metathesis reactions, including the cross-metathesis reactions described in detail herein.
  • the present complexes tolerate a greater diversity of functional groups and are more stable to air and moisture.
  • the present complexes allow an olefinic reactant to be substituted with a functional group without compromising the efficiency or selectivity of a metathesis reaction involving that olefin.
  • the present invention also allows the second reactant, i.e., the olefin metathesis partner, to be substituted with a functional group.
  • the functional group may or may not be a ligand for the metal complex; the present method is not limited in this regard.
  • the ruthenium carbene complexes of the invention find utility in effecting a variety of asymmetric metathesis reactions including, but not limited to, enantioselective ring-closing metathesis, asymmetric desymmetrization of meso -trienes, enantioselective cross-metathesis, enantioselective ring-opening/cross metathesis, enantioselective ring-opening/ring-closing metathesis, and kinetic resolution of racemic mixtures of chiral olefins.
  • a chiral ligand such as a 1,3-disubstituted-4,5-dihydro-(4,5-disubstituted)-imidazol-2-ylidene
  • a phosphine ligand in a bisphosphine-ligated ruthenium alkylidene complex provides for the generation of a series of novel chiral ruthenium olefin metathesis complexes. These complexes have been shown to exhibit high enantioselectivity in a variety of olefin metathesis reactions.
  • the complexes exhibit relatively high functional-group tolerance and relatively high stability in the presence of water, oxygen, ionic liquids, protic solvents, and a variety of common impurities.
  • This functional-group tolerance and enhanced stability allow for the effective transformation of substrates inaccessible with previously reported chiral molybdenum metathesis catalysts.
  • Alicyclic refers to an aliphatic cyclic moiety, which may or may not be bicyclic or polycyclic.
  • Alkenyl refers to a linear, branched or cyclic hydrocarbon group of about 2-20 carbon atoms containing at least one double bond, such as ethenyl, n -propenyl, isopropenyl, n -butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl.
  • Preferred alkenyl groups herein contain about 2-12 carbon atoms.
  • lower alkenyl intends an alkenyl group of 2 to 6 carbon atoms
  • specific term “cycloalkenyl” intends a cyclic alkenyl group, preferably having about 5-8 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom-containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkenyl” and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
  • Alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be represented as -O-alkyl where alkyl is as defined above.
  • a "lower alkoxy” group intends an alkoxy group containing about 1-6 carbon atoms.
  • alkenyloxy and lower alkenyloxy respectively refer to an alkenyl and lower alkenyl group bound through a single, terminal ether linkage
  • alkynyloxy and “lower alkynyloxy” respectively refer to an alkynyl and lower alkynyl group bound through a single, terminal ether linkage.
  • Alkoxycarbonyl refers to the substituent -COOR, where R is an alkyl group as defined herein.
  • Alkyl refers to a linear, branched or cyclic saturated hydrocarbon group typically although not necessarily containing about 1-20 carbon atoms (C 1-20 alkyl), such as methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, t -butyl, octyl, decyl, as well as cycloalkyl groups such as cyclopentyl, and cyclohexyl.
  • alkyl groups herein contain about 1-12 carbon atoms and typically about 1-10 carbon atoms.
  • lower alkyl intends an alkyl group of about 1-6 carbon atoms
  • cycloalkyl intends a cyclic alkyl group, typically having about 4-8, preferably about 5-7, carbon atoms.
  • substituted alkyl refers to alkyl substituted with one or more substituent groups
  • heteroatom-containing alkyl and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively.
  • Alkyldiketonate refers to an alkyl group as defined herein, having two ketone carbonyl groups. Typically the alkyl will have from 3-30 carbon atoms.
  • Alkylene refers to a difunctional linear, branched or cyclic alkyl group, where "alkyl” is as defined above.
  • Alkylsulfanyl refers to the group -S-R, where R is an alkyl group.
  • Alkylsulfinyl refers to the group -SO-R, where R is an alkyl group.
  • Alkylsulfonato refers to the group -S(O) 3 -R, where R is an alkyl group.
  • Alkylsulfonyl refers to the group -S(O) 2 -R, where R is an alkyl group.
  • Alkynyl refers to a linear or branched hydrocarbon group of 2 to 20 carbon atoms containing at least one triple bond, such as ethynyl or n -propynyl. Preferred alkynyl groups herein contain 2 to 12 carbon atoms.
  • the term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkynyl” and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • Amino is used herein to refer to the group -NR'R", where each of R' and R" is independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl and heterocyclic.
  • Alkyl refers to an alkyl group with an aryl substituent
  • aralkylene refers to an alkylene group with an aryl substituent
  • alkaryl refers to an aryl group that has an alkyl substituent
  • alkarylene refers to an arylene group with an alkyl substituent
  • Aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Preferred aryl groups contain one aromatic ring or 2 to 4 fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl.
  • Substituted aryl refers to an aryl moiety substituted with one or more substituent groups
  • heteroatom-containing aryl and “heteroaryl” refer to aryl in which at least one carbon atom is replaced with a heteroatom. Typically the heteroaryl will contain 1-2 heteroatoms and 3-19 carbon atoms.
  • the terms “aryl” and “aromatic” includes heteroaromatic, substituted aromatic, and substituted heteroaromatic species.
  • Aryldiketonate refers to an aryl group, as defined herein, having two ketone carbonyl groups.
  • Aryloxy refers to an aryl group bound through a single, terminal ether linkage.
  • An "aryloxy” group may be represented as -O-aryl, where aryl is as defined herein.
  • Arylsulfonato refers to the group the group -S(O) 3 -aryl, where aryl is as defined herein.
  • Carboxy refers to the group - COOH.
  • Carboxylate is intended to mean the group -COO - .
  • cyclic group is intended to refer to any aliphatic or aromatic structure, and may contain substituents and/or heteroatoms. Typically although not necessarily a cyclic group is a 4-2 membered ring, preferably a 5- to 8-membered ring.
  • “Functional groups” (also referred to as “Fn”) refer to groups such as halo, phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, sulfinyl, C 1-20 alkylsulfanyl, C 5-20 arylsulfanyl, C 1-20 alkylsulfonyl, C 5-20 arylsulfonyl, C 1-20 alkylsulfinyl, C 5-20 arylsulfinyl, sulfonamide, amino, amido, imino, nitro, nitroso, hydroxyl, C 1-20 alkoxy, C 2-20 alkenyloxy, C 2-20 alkynyloxy, C 5-20 aryloxy, C 1-20 carboxylato, C 2-20 alkylcarboxylato, C 5-20 arylcarboxylato, C 2-20 alkoxycarbonyl, C 5-20 aryloxycarbony
  • Functional groups can also be substituted with one or more moieties selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, aryl, hydroxyl, sulfhydryl, -(CO)-H, halo, as well as other functional groups.
  • the term "functional group” is intended to include the functional group per se, as well as any linker group.
  • Halo and halogen are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
  • haloalkyl refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
  • Heteroatom-containing as in a “heteroatom-containing hydrocarbyl group” refers to a hydrocarbon molecule or a hydrocarbyl molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom-containing
  • heteroaryl and heteroaromatic
  • a “heterocyclic” group or compound may or may not be aromatic, and further that “heterocycles” may be monocyclic, bicyclic, or polycyclic as described above with respect to the term “aryl.”
  • Hydrocarbyl refers to univalent hydrocarbyl radicals containing about 1-30 carbon atoms, preferably about 1-20 carbon atoms, most preferably about 1-12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as alkyl groups, alkenyl groups, alkynyl groups, alicyclic groups, aryl groups, aralkyl groups, and alkaryl groups.
  • lower hydrocarbyl intends a hydrocarbyl group of about 1-6 carbon atoms
  • hydrocarbylene intends a divalent hydrocarbyl moiety containing about 1-30 carbon atoms, preferably about 1-20 carbon atoms, most preferably about 1-12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species.
  • lower hydrocarbylene intends a hydrocarbylene group of about 1-6 carbon atoms.
  • Substituted hydrocarbyl refers to hydrocarbyl substituted with one or more substituent groups
  • heteroatom-containing hydrocarbyl and “heterohydrocarbyl” refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom
  • substituted hydrocarbylene refers to hydrocarbylene substituted with one or more substituent groups
  • heteroatom-containing hydrocarbylene and heterohydrocarbylene refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom.
  • Optional or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • silyl is intended to mean a silyl group (-SiH 3 ) or derivative thereof.
  • the term silyl can thus be represented by the formula -SiR 3 , where each R group is independently H, alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl.
  • Stepselective refers to a chemical reaction that preferentially results in one stereoisomer relative to a second stereoisomer, i.e., gives rise to a product in which the ratio of a desired stereoisomer to a less desired stereoisomer is greater than 1:1.
  • Substituted as in “substituted hydrocarbyl,” “substituted alkyl,” “substituted aryl,” as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety at least one hydrogen atom bound to a carbon atom is replaced with one or more non-hydrogen substituents.
  • substituents include, without limitation functional groups ("Fn") as defined above; and hydrocarbyl moieties such as C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 5-20 aryl, C 5-30 aralkyl, and C 5-30 alkaryl.
  • the aforementioned functional groups and hydrocarbyl moieties may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above.
  • substituted appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group.
  • substituted alkyl, alkenyl and alkynyl is to be interpreted as “substituted alkyl, substituted alkenyl and substituted alkynyl.”
  • optionally substituted alkyl, alkenyl and alkynyl is to be interpreted as “optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.”
  • the ruthenium carbene complexes of the invention have the formula
  • X 1 and X 2 are independently selected from the group consisting of anionic ligands and polymers, or X 1 and X 2 may be taken together to form a cyclic group, typically although not necessarily a 5- to 8-membered ring.
  • X 1 and X 2 are independently selected from the group consisting of hydrogen, halo, C 1-20 alkyl, C 5-20 aryl, C 1-20 alkoxy, C 5-20 aryloxy, C 3-20 alkyldiketonate, C 5-20 aryldiketonate, C 2-20 alkoxycarbonyl, C 5-20 aryloxycarbonyl, C 2-20 acyl, C 1-20 alkylsulfonato, C 5-20 arylsulfonato, C 1-20 alkylsulfanyl, C 5-20 arylsulfanyl, C 1-20 alkylsulfinyl, and C 5-20 arylsulfinyl.
  • X 1 and X 2 are substituted with one or more moieties selected from the group consisting of C 1-20 alkyl, C 1-20 alkoxy, aryl, and halo, which may, in turn, with the exception of halo, be further substituted with one or more groups selected from halo, C 1-6 alkyl, C 1-6 alkoxy, and phenyl.
  • X 1 and X 2 are halo, benzoate, C 2-6 acyl, C 2-6 alkoxycarbonyl, C 1-6 alkyl, phenoxy, C 1-6 alkoxy, C 1-6 alkylsulfanyl, aryl, and C 1-6 alkylsulfonyl.
  • X 1 and X 2 are each halo, CF 3 CO 2 , CH 3 CO 2 , CFH 2 CO 2 , (CH 3 ) 3 CO, (CF 3 ) 2 (CH 3 )CO, (CF 3 )(CH 3 ) .2 CO, PhO, MeO, EtO, tosylate, mesylate, or trifluoromethanesulfonate.
  • X 1 and X 2 are each halo, preferably chloro.
  • the complex may also comprise (i.e., be bound to) a solid support, such as a polymeric substrate, i.e., at least one of X 1 and X 2 can be a polymer.
  • a polymeric substrate i.e., at least one of X 1 and X 2 can be a polymer.
  • Such a polymer will also comprise an appropriate linker, by which attachment to the remainder of the complex may be effected.
  • the polymer is at one of the R 5 and R 6 positions.
  • R 1 is selected from the group consisting of hydrogen, silyl, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and carboxyl. In a preferred embodiment, R 1 is hydrogen or C 5-20 aryl.
  • R 2 is selected from the group consisting of hydrogen, silyl, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or R 1 and R 2 may be taken together to form a cyclic group.
  • the R 2 substituent is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, and C 5-20 aryl. More preferably, R 2 is phenyl, vinyl, methyl, isopropyl, or t -butyl, optionally substituted with one or more moieties selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, phenyl, and a functional group Fn.
  • R 2 is phenyl or vinyl substituted with one or more moieties selected from the group consisting of methyl, ethyl, chloro, bromo, iodo, fluoro, nitro, dimethylamino, methoxy, and phenyl.
  • R 1 and R 2 are taken together to form a cyclic group, which may be aliphatic or aromatic, and may contain substituents and/or heteroatoms. Generally, such a cyclic group will contain 4 to 12, preferably 5 to 8, ring atoms.
  • Y 1 and Y 2 are heteroatoms independently selected from the group consisting of N, O, S, and P. In a preferred embodiment, Y 1 and Y 2 are the same. In another preferred embodiment Y 1 and Y 2 are nitrogen.
  • the O and S heteroatoms are divalent, and therefore, it is understood that when either Y 1 and Y 2 is O or S, then the appended aryl group is absent.
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-20 alkyl, substituted C 1-20 alkyl, perfluoronated C 1-20 alkyl (an alkyl chain that is saturated with fluorine atoms instead of hydrogen atoms), C 1-20 heteroalkyl, substituted C 1-20 heteroalkyl, C 1-20 alkoxy, C 5-20 aryl, substituted C 5-20 aryl, heteroaryl, C 5-30 aralkyl, C 5-30 alkaryl, and halo.
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, halo, phenyl, and lower alkyl-substituted phenyl (e.g. dimethylphenyl). In yet another embodiment, R 20 and R 21 are each methyl.
  • Such carbene ligands provide for complexes that are highly enantioselective metathesis catalysts.
  • the complex may also comprise a solid support, such as a polymeric substrate.
  • a polymeric substrate such as a polymeric substrate.
  • Such a polymer will also comprise an appropriate linker, by which attachment to the remainder of the complex may be effected.
  • R 5 and R 6 are independently selected from the group consisting of polymers, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, optionally substituted with one or more moieties selected from the group consisting of C 1-20 alkyl, C 1-10 alkoxy, C 5-20 aryl, hydroxyl, sulfhydryl, -(CO)-H, halide, and functional groups.
  • R 5 and R 6 are independently selected from the group consisting of C 1-10 alkyl (e.g., t -butyl), C 5-20 aryl, cyclohexyl, mesityl, and lower alkyl substituted phenyl. Exemplary R 5 and R 6 are shown below:
  • R 5 and R 6 are linked together to form a substituted or unsubstituted, saturated or unsaturated ring structure, e.g. a C 4-12 alicyclic group or a C 5-6 aryl group, which may itself be substituted, e.g., with linked or fused alicyclic or aromatic groups, or with other substituents.
  • a substituted or unsubstituted, saturated or unsaturated ring structure e.g. a C 4-12 alicyclic group or a C 5-6 aryl group, which may itself be substituted, e.g., with linked or fused alicyclic or aromatic groups, or with other substituents.
  • the complex may also comprise a solid support, such as a polymeric substrate, i.e., at least one of R 5 and R 6 can be a polymer.
  • a polymeric substrate i.e., at least one of R 5 and R 6 can be a polymer.
  • Such a polymer will also comprise an appropriate linker, by which attachment to the remainder of the complex may be effected.
  • L is a neutral electron donor ligand, and may or may not be linked to R 2 , X 1 , and/or X 2 through a spacer moiety.
  • suitable L moieties include, without limitation, phosphine, sulfonated phosphine, phosphite, phosphinite, phosphonite, arsine, stibine, ether (including cyclic ethers), amino, amido, imino, sulfoxide, carboxy, nitrosyl, pyridyl, substituted pyridyl (e.g., halogenated pyridyl), imidazolyl, substituted imidazolyl (e.g., halogenated imidazolyl), pyrazinyl (e.g., substituted pyrazinyl), and thioether.
  • L is a phosphine of the formula PR'R"R'", where R', R", and R'" are each independently C 1-10 alkyl (particularly primary alkyl, secondary alkyl or cycloalkyl), C 5-20 aryl or a heteroatom-containing functional group.
  • R', R", and R'" are the same, for example, -P(cyclohexyl) 3 , -P(cyclopentyl) 3 , -P(isopropyl) 3 , -P(phenyl) 3 .
  • L is -P(phenyl) 2 (R) or-P(phenyl)(R) 2 , where R is C 1-20 alkyl, typically lower alkyl.
  • weaker ligands such as the nitrogen-containing heterocycles, which enhance catalytic activity presumably because of the requirement that the L ligand be lost for initiation to occur. Examples of complexes wherein L and R 2 are linked include the following:
  • any two or more of X 1 , X 2 , L, R 1 , R 2 , R 5 and R 6 of the complex can be taken together to form a chelating multidentate ligand, as described , for example, in Grubbs et al., U.S. Patent No. 5,312,940 .
  • bidentate ligands include, but are not limited to, bisphosphines, dialkoxides, alkyldiketonates, and aryldiketonates.
  • Specific examples include -P(Ph) 2 CH 2 CH 2 P(Ph) 2 -, -As(Ph) 2 CH 2 CH 2 As(Ph 2 )-, -P(Ph) 2 CH 2 CH 2 C(CF 3 ) 2 O-, binaphtholate dianions, pinacolate dianions, -P(CH 3 ) 2 (CH 2 ) 2 P(CH 3 ) 2 - and -OC(CH 3 ) 2 (CH 3 ) 2 CO-.
  • Preferred bidentate ligands are -P(Ph) 2 CH 2 CH 2 P(Ph) 2 - and -P(CH 3 ) 2 (CH 2 ) 2 P(CH 3 ) 2 -.
  • Tridentate ligands include, but are not limited to, (CH 3 ) 2 NCH 2 CH 2 P(Ph)CH 2 CH 2 N(CH 3 ) 2 .
  • Other preferred tridentate ligands are those in which any three of X 1 , X 2 , L, R 1 , R 2 , R 5 and R 6 (e.g.
  • X 1 , L, and any of R 5 and R 6 are taken together to be cyclopentadienyl, indenyl or fluorenyl, each optionally substituted with C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkyl, C 5-20 aryl, C 1-20 alkoxy, C 2-20 alkenyloxy, C 2-20 alkynyloxy, C 5-20 aryloxy, C 2-20 alkoxycarbonyl, C 1-20 alkylsulfanyl, C 1-20 alkylsulfonyl, or C 1-20 alkylsulfinyl, each of which may be further substituted with C 1-6 alkyl, halo, C 1-6 alkoxy or with a phenyl group optionally substituted with halo, C 1-6 alkyl or C 1-6 alkoxy.
  • X 1 , L, and any one of R 5 and R 6 are taken together to be cyclopentadienyl, optionally substituted with vinyl, hydrogen, Me or Ph.
  • Tetradentate ligands include, but ate not limited to O 2 C(CH 2 ) 2 P(Ph)(CH 2 ) 2 P(Ph)(CH 2 ) 2 CO 2 , phthalocyanines, and porphyrins.
  • ruthenium carbene complex further comprises a second neutral electron donor ligand (L') attached to ruthenium.
  • Ligands containing bulky, electron-donating groups provide for very highly active olefin metathesis catalysts. Such catalysts are thus suitable to catalyze reactions for which other, less active catalysts are ineffective, and are also useful in enhancing the stereoselectivity of a catalyzed cross-metathesis reaction.
  • the catalyst useful in conjunction with the present methods is therefore the ruthenium carbene complex of the formula (VII):
  • X 1 and X 2 are independently selected from the group consisting of anionic ligands and polymers, or X 1 and X 2 may be taken together to form a cyclic group. Preferred X 1 and X 2 groups are identified above. X 1 and X 2 are most preferably halo.
  • R 1 is selected from the group consisting of hydrogen, silyl, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and carboxyl. Preferred R 1 groups are as identified above. R 1 is most preferably hydrogen.
  • R 2 is selected from the group consisting of hydrogen, silyl, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl or R 1 and R 2 may be taken together to form a cyclic group.
  • Preferred R 2 groups are as identified above.
  • R 2 is preferably C 5-20 aryl, most preferably phenyl.
  • Y 1 and Y 2 are heteroatoms independently selected from the group consisting of N, O, S, and P.
  • Preferred Y 1 and Y 2 groups are as identified above.
  • Y 1 and Y 2 are preferably the same, and most preferably nitrogen.
  • the O and S heteroatoms are divalent, and therefore, it is understood that when either Y 1 and Y 2 is O or S, then the appended aryl group is absent.
  • R 5 and R 6 are independently selected from the group consisting of polymers, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, optionally substituted with one or more moieties selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, C 5-20 aryl, hydroxyl, sulfhydryl, -(CO)-H, halo, and functional groups.
  • Preferred R 5 and R 6 groups are as identified above.
  • R 5 and R 6 are most preferably C 5-20 aryl groups.
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-20 alkyl, substituted C 1-20 alkyl, perfluoronated C 1-20 alkyl, C 1-20 heteroalkyl, substituted C 1-20 heteroalkyl, C 1-20 alkoxy, C 5-20 aryl, substituted C 5-20 aryl, heteroaryl, C 5-30 aralkyl, C 5-30 alkaryl, and halo.
  • the R 20 and R 21 are preferably in the anti-position relative to R 5 and R 6 .
  • R 20 is an alkyl
  • R 21 is hydrogen.
  • R 20 and R 21 are alkyl groups.
  • L is a neutral electron donor ligand.
  • Preferred L groups are as identified above.
  • L is a phosphine having the formula PR'R"R"', where R', R", and R'" are each independently selected from the group consisting of C 1-10 alkyl and C 5-20 aryl.
  • L is selected from the group consisting of-P(cyclohexyl) 3 , -P(cyclopentyl) 3 , -P(isopropyl) 3 , -P(phenyl) 3 ,- P(phenyl) 2 (R) and-P(phenyl)(R) 2 , where R is alkyl.
  • Synthesis of the enatiomerically pure complexes of the invention begins with a compound such as a commercially available 1,2-diamine (1) such as (1 R, 2 R )-1,2-diaminocyclohexane or (1 R ,2 R )-diphenylethylenediamine, or similar diamines that are readily synthesized, such as di- t -butylethylenediamine, diadamantylethylenediamine, dimesitylethylenediamine, and so forth.
  • 1,2-diamine (1) such as (1 R, 2 R )-1,2-diaminocyclohexane or (1 R ,2 R )-diphenylethylenediamine, or similar diamines that are readily synthesized, such as di- t -butylethylenediamine, diadamantylethylenediamine, dimesitylethylenediamine, and so forth.
  • an N-aryl substituent can be introduced by reaction with an aryl halide through standard Pd-coupling reactions ( Wolfe et al., J. Org. Chem. 65:1144-1157 (2000 )).
  • an aldehyde or ketone can be condensed with the diamine and reduced in order to yield the desired product:
  • the resulting secondary amine is then condensed with a compound such as CH(Lg) 3 wherein Lg is a substituent displaceable by a nucleophile (e.g., triethyl orthoformate), and a salt having the formula X + Y - , such as an ammonium salt (e.g., ammonium tetrafluoroborate) to produce the corresponding imidazolium tetrafluoroborate salt (4) ( Saba et al., Tetrahedron Lett. 32:5031-5034 (1991 )):
  • a strong base such as sodium or potassium tert- butoxide or hexafluoro- ter t-butoxide, e.g., potassium hexafluoro- tert -butoxide
  • the chiral ruthenium carbene complexes of the invention find particular utility as catalysts in effecting a host of enantioselective organic transformations.
  • these complexes can be used to control the enantioselectivity of an olefin metathesis reaction by catalyzing the reaction with a chiral ruthenium carbene complex of the invention.
  • these complexes can be treated with MX reagents, where M is an alkali metal and X can be any negatively charged counterion (e.g., Br - or I - ) in order to effect higher relative rates of enantioselectivity.
  • reaction of the neutral complex with lithium bromide or sodium iodide generates the bromide and iodide analogs of the complex, resulting in catalysts that exhibit enhanced enantioselectivity relative to the chloro counterpart (reaction with MX reagents should lead to exchange of the chloride groups for X groups without any change in charge).
  • a meso-triene or achiral triene can undergo asymmetric ring-closing metathesis to afford optically-enriched substituted cyclic or heterocyclic olefins in a reaction catalyzed by the complex of the invention:
  • the complex of the invention may be used to treat a cyclic olefin substituted with two terminal olefin groups, to effect an enantioselective ring-opening/ring-closing metathesis reaction and thereby provide an optically enriched cyclic olefin:
  • the complex of the invention can effect the ring-opening/cross metathesis between a cyclic and an acyclic olefin to afford an optically enriched product:
  • the complex of the invention can effect a kinetic resolution via the enantioselective cross metathesis of a racemic mixture of a chiral olefin with another olefinic reactant, to afford an opticallyactive product and starting material:
  • the complex of the invention can also be used to effect kinetic resolutions through the enantioselective ring-closing of a racemic diene, affording partial conversion to an optically enriched sample of the starting material and an optically enriched cyclic olefin product:
  • the resulting diamines ( 3a, 3b, 3c, 4a, 4b, 4c ) are then condensed with triethyl orthoformate and ammonium tetrafluoroborate to produce the corresponding imidazolium tetrafluoroborate salts ( 5a, 5b, 5c, 6a, 6b, 6c ) ( Saba et al., Tetrahedron Lett. 32:5031-5034 (1991 )):
  • imidazolium salt ( 6b ) (0.200 g, 0.408 mmol) and potassium hexafluoro- t -butoxide (0.108 g, 0.490 mmol) were dissolved in tetrahydrofuran (4 mL), added to a solution of bis(tricyclohexylphosphine)-benzylidene ruthenium dichloride (0.403 g, 0.490 mmol) in toluene (10 mL), and transferred to a Schlenk flask. The flask was removed from the glove box and heated to 50°C under argon for 2 hours. The solution was cooled to ambient temperature and the volatiles were removed in vacuo.
  • Substrates ( 10 ), ( 11 ), and ( 12 ) monosubstituted central olefin with which the catalyst undergoes the initial metathesis reaction ( Ulman et al., Organometallics 17:2484-2489 (1998 )), and two di- or trisubstituted pendant olefins with which the stereochemically defining cyclization step occurs.
  • catalysts prepared from (1 R ,2 R )-diphenylethylenediamine ( 8a, 8b, 8c ) exhibit higher enantioselectivity (up to 23% ee) than those prepared from (1 R ,2 R )-1,2-diaminocyclohexane ( 7a, 7b, 7c ) ( ⁇ 9% ee).
  • the conditions were as follows: 2.5 mol % of catalyst, 55 mM substrate in CH 2 Cl 2 , 38°C.
  • conditions were: 5 mol % of catalyst, 100 mol % of halide salt, 55 mM substrate in THF, 38°C.
  • the halide ligand is bound trans to the L-type ligand.
  • the halides adopt a cis arrangement in the alkylidene-halide-olefin plane.
  • the olefin binds trans to the L-type ligand.
  • C is inconsistent with the observed stereochemical outcome of the desymmetrization of substrates 10,11 and 12.
  • geometry (B) cannot be discounted, geometry (A) appears to be most consistent with the observed ligand effects and stereochemical outcome of these reactions.
  • the unbound olefin occupies the distal position relative to the apical halide; this proposed steric interaction between the unbound olefin and apical halide is further consistent with the dramatic increase in enantioselectivity observed upon changing the halide from Cl - to Br - to I -. Further details on the stereochemical model can be found in Seiders, et al., Organic Letters 3(20):3225-3228 (2001 ).
  • Asymmetric cross metathesis provides a powerful means for the formation of stereogenic centers under catalytic and mild conditions starting form readily available olefinic starting materials.
  • the chiral ligand provides a steric bias that directs the face from which the incoming olefin will approach the catalyst after the substrate is already bound to the catalyst. The enantiomeric excess is then determined by the difference in the relative energies of the two possible cyclic transition states that lead to the cyclic products, not by the initial binding of the substrate.
  • the ligand In asymmetric olefin cross metathesis, the ligand not only needs to designate the face from which the cross partner will access the catalyst, but also needs to directly interact with the cross partner during the binding event such that one enantiomer (or one enantiotopic olefin in the case of a desymmetrization) will be preferred. This requires a greater degree of control in the olefin binding event.
  • the catalysts of the invention effectively impart the desired facial selectivity. It is proposed that inclusion of steric bulk at the meta position, opposite to the ortho group already present, will impart a greater steric influence on the binding of the chiral/prochiral substrates without interfering with the highly effective transmission of chirality from the backbone to the aniline derived aromatic groups.
  • the catalysts were prepared from commercially available and or readily synthesized starting materials, e.g., 1-bromo-2,5-diisopropylbenzene.
  • starting materials e.g., 1-bromo-2,5-diisopropylbenzene.
  • palladium mediated coupling of 1-bromo-2,5-diisopropylbenzene to (1 R ,2 R )-diphenyl ethylene diamines afforded the diarylated product in good yield.
  • Conversion to the tetrafluoroborate salt occurred without event.
  • excess of the chiral ligand was employed to ease in the purification.

Claims (23)

  1. Complexe de carbène de ruthénium chiral de la formule :
    Figure imgb0049
     dans laquelle :
    X1 et X2 sont indépendamment choisis dans le groupe constitué par les ligands anioniques et les polymères, ou bien X1 et X2 peuvent être pris ensemble pour former un groupe cyclique ;
    R1 est choisi dans le groupe constitué par l'hydrogène et les groupements silyle, hydrocarbyle, hydrocarbyle substitués, hydrocarbyle contenant des hétéroatomes, hydrocarbyle substitués contenant des hétéroatomes, et carboxyle ;
    R2 est choisi dans le groupe constitué par l'hydrogène et les groupements silyle, hydrocarbyle, hydrocarbyle substitués, hydrocarbyle contenant des hétéroatomes, et hydrocarbyle substitués contenant des hétéroatomes, ou bien R1 et R2 peuvent être pris ensemble pour former un groupe cyclique ;
    Y1 et Y2 sont des hétéroatomes indépendamment choisis dans le groupe constitué par N, O, S, et P, à condition que lorsque Y1 ou Y2 est O ou S, alors le groupe aryle attaché soit absent ;
    R5 et R6 sont indépendamment choisis dans le groupe constitué par les polymères, les groupements hydrocarbyle, hydrocarbyle substitués, hydrocarbyle contenant des hétéroatomes, hydrocarbyle substitués contenant des hétéroatomes, et les groupes fonctionnels, éventuellement substitués par un ou plusieurs groupements choisis dans le groupe constitué par les groupements alkyle en C1-10, alcoxy en C1-10, aryle en C5-20, hydroxyle, sulfhydryle, -(CO)-H, halogéno, et les groupes fonctionnels ; ou bien
    R5 et R6 sont liés pour former une structure cyclique substituée ou non substituée, saturée ou insaturée, qui peut elle-même être substituée ;
    R20 et R21 sont indépendamment choisis dans le groupe constitué par l'hydrogène et les groupements alkyle en C1-20, alkyle en C1-20 substitués, alkyle en C1-20 perfluorés, hétéroalkyle en C1-20, hétéroalkyle en C1-20 substitués, alcoxy en C1-20, aryle en C5-20, aryle en C5-20 substitués, hétéroaryle, aralkyle en C5-30, alkaryle en C5-30, et halogéno ; et
    L est un ligand donneur d'électrons neutre.
  2. Complexe de la revendication 1 dans lequel X1 et X2 sont indépendamment choisis dans le groupe constitué par les groupements halogéno, benzoate, acyle en C2-6, (alcoxy en C2-6)carbonyle, alkyle en C1-6, phénoxy, alcoxy en C1-6, (alkyl en C1-6)sulfanyle, aryle en C5-20, et (alkyl en C1-6)sulfonyle.
  3. Complexe de la revendication 2 dans lequel X1 et X2 sont indépendamment choisis dans le groupe constitué par les groupements halogéno, CF3CO2, CH3CO2, CFH2CO2, (CH3)3CO, (CF3)2(CH3)CO, (CF3)(CH3)2CO, PhO, MeO, EtO, tosylate, mésylate, et trifluorométhanesulfonate.
  4. Complexe de la revendication 3 dans lequel X1 et X2 sont des halogènes.
  5. Complexe de la revendication 1 dans lequel R1 est choisi dans le groupe constitué par l'hydrogène et les groupements aryle en C5-20.
  6. Complexe de la revendication 1 dans lequel R2 est un groupement aryle en C5-20.
  7. Complexe de la revendication 6 dans lequel R2 est un groupement phényle.
  8. Complexe de la revendication 1 dans lequel Y1 et Y2 représentent N.
  9. Complexe de la revendication 1 dans lequel R5 et R6 sont des groupements aryle en C5-20.
  10. Complexe de la revendication 1 dans lequel R20 est un groupement alkyle et R21 est un hydrogène.
  11. Complexe de la revendication 1 dans lequel R20 et R21 sont des groupements alkyle.
  12. Complexe de la revendication 1 dans lequel L est choisi dans le groupe constitué par les ligands phosphine, phosphine sulfonée, phosphite, phosphinite, phosphonite, arsine, stibine, éther, amino, amido, imino, sulfoxyde, carboxy, nitrosyle, pyridyle, pyridyle substitué, imidazolyle, imidazolyle substitué, pyrazinyle, et thioéther.
  13. Complexe de la revendication 12 dans lequel L est une phosphine ayant la formule PR'R"R"' où R', R" et R''' sont chacun indépendamment choisi dans le groupe constitué par un groupement alkyle en C1-10, un groupement aryle en C5-20, et un groupe fonctionnel contenant des hétéroatomes.
  14. Complexe de la revendication 13 dans lequel R', R" et R''' sont identiques.
  15. Complexe de la revendication 14 dans lequel L est choisi dans le groupe constitué par les ligands -P(cyclohexyle)3, -P(cyclopentyle)3, -P(isopropyle)3, et -P(phényle)3.
  16. Complexe de la revendication 13 dans lequel L est une phosphine ayant la formule -P(phényl)2(R) ou -P(phényl)(R)2, où R est un groupement alkyle en C1-20.
  17. Complexe de la revendication 1 dans lequel R5 et R6 sont liés pour former une structure cyclique substituée ou non substituée, saturée ou insaturée, qui est un groupe alicyclique en C4-12 ou un groupe aryle en C5-6, qui peut lui-même être substitué par des groupes alicycliques ou aromatiques liés ou fusionnés, ou par d'autres substituants.
  18. Procédé de contrôle de l'énantiosélectivité d'une réaction de métathèse d'oléfines comprenant la catalyse de la réaction avec un complexe de carbène de ruthénium chiral de la formule :
    Figure imgb0050
     dans laquelle :
    X1 et X2 sont indépendamment choisis dans le groupe constitué par les ligands anioniques et les polymères, ou bien X1 et X2 peuvent être pris ensemble pour former un groupe cyclique ;
    R1 est choisi dans le groupe constitué par l'hydrogène et les groupements silyle, hydrocarbyle, hydrocarbyle substitués, hydrocarbyle contenant des hétéroatomes, hydrocarbyle substitués contenant des hétéroatomes, et carboxyle ;
    R2 est choisi dans le groupe constitué par l'hydrogène et les groupements silyle, hydrocarbyle, hydrocarbyle substitués, hydrocarbyle contenant des hétéroatomes, et hydrocarbyle substitués contenant des hétéroatomes, ou bien R1 et R2 peuvent être pris ensemble pour former un groupe cyclique ;
    Y1 et Y2 sont des hétéroatomes indépendamment choisis dans le groupe constitué par N, O, S, et P, à condition que lorsque Y1 ou Y2 est O ou S, alors le groupe aryle attaché soit absent ;
    R5 et R6 sont indépendamment choisis dans le groupe constitué par les polymères, les groupements hydrocarbyle, hydrocarbyle substitués, hydrocarbyle contenant des hétéroatomes, hydrocarbyle substitués contenant des hétéroatomes, et les groupes fonctionnels, éventuellement substitués par un ou plusieurs groupements choisis dans le groupe constitué par les groupements alkyle en C1-10, alcoxy en C1-10, aryle en C5-20, hydroxyle, sulfhydryle, -(CO)-H, halogéno, et les groupes fonctionnels ; ou bien
    R5 et R6 sont liés pour former une structure cyclique substituée ou non substituée, saturée ou insaturée, qui peut elle-même être substituée ;
    R20 et R21 sont indépendamment choisis dans le groupe constitué par l'hydrogène et les groupements alkyle en C1-20, alkyle en C1-20 substitués, alkyle en C1-20 perfluorés, hétéroalkyle en C1-20, hétéroalkyle en C1-20 substitués, alcoxy en C1-20, aryle en C5-20, aryle en C5-20 substitués, hétéroaryle, aralkyle en C5-30, alkaryle en C5-30, et halogéno ; et
    L est un ligand donneur d'électrons neutre.
  19. Procédé de la revendication 18 dans lequel la réaction de métathèse d'oléfines est la désymétrisation de triènes achiraux.
  20. Procédé de la revendication 18 dans lequel la réaction de métathèse d'oléfines est la désymétrisation énantiosélective de triènes.
  21. Procédé de la revendication 18 dans lequel la réaction de métathèse d'oléfines est une métathèse de fermeture de cycle asymétrique.
  22. Procédé de la revendication 18 qui comprend en outre le traitement du complexe avec un réactif de la formule NaX, où X est un contre-ion chargé négativement.
  23. Procédé de la revendication 22 dans lequel X est choisi dans le groupe constitué par Br- et I-.
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WO2002083742A2 (fr) 2002-10-24
EP1395616A4 (fr) 2006-11-22
US7683180B2 (en) 2010-03-23
WO2002083742A3 (fr) 2002-12-19
AU2002307384A1 (en) 2002-10-28
EP1395616A2 (fr) 2004-03-10

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